Our laboratory seeks to understand signaling mechanisms underlying cardiovascular biology and disease, thereby generating new therapeutic strategies and molecular targets. We have focused on the mechanisms by which thrombin activates platelets and other cells. The cloning and characterization of a thrombin receptor provided a major step forward in our understanding of thrombin signaling. The novel proteolytic mechanism of receptor activation raised many exciting new questions. In particular, the irreversibility of this activation mechanism placed particular emphasis on understanding how the thrombin receptor is shut off. The goal of this proposal is to elucidate the molecular mechanisms by which thrombin receptor signaling is terminated. These studies will point up novel strategies for manipulating signaling by thrombin receptor and other members of this receptor family. Health relevance includes the possible identification of genetic new risk factors for thrombosis and vascular diseases as well as new therapeutic approaches for these disorders.